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Porphyrias: a review and case report. Anemia MCV=HCT/RBC 80-100 <80 >100 Microcytic Sudden massive blood lose Marrow failure hemolysis Megaloblastic anemia.

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Presentation on theme: "Porphyrias: a review and case report. Anemia MCV=HCT/RBC 80-100 <80 >100 Microcytic Sudden massive blood lose Marrow failure hemolysis Megaloblastic anemia."— Presentation transcript:

1 Porphyrias: a review and case report

2 Anemia MCV=HCT/RBC <80 >100 Microcytic Sudden massive blood lose Marrow failure hemolysis Megaloblastic anemia Spurious macrocytic anemia

3 Microcytic anemia Defect in hemoglobin synthesis 3-dimensional structure of hemoglobin. The four subunits are shown in red and yellow, and the heme groups in green.

4 Microcytic anemia Defect in hemoglobin sythesis Iron binding capacityLow or normalHigh Low or normalIron Iron deficiency Defect in: Porphyrin synthesis Heme synthesis Globin synthesis

5 Defect in: Porphyrin synthesis Heme synthesis Globin synthesis Hemoglobin electrophoresis Abnormal Normal Defect in: Porphyrin synthesis Heme synthesis Defect in: Globin synthesis QuantitativeQualitativeBoth ThalassemiaSickle-thalS,C,F,ect

6 Heme Non-erythroidErythroid Haemoproteins Haemoglobin Electron transfer and energy trapping myoglobinCytochromesOthers

7 Porphyrins synthesis URO I Spontaneous COPRO I MitochondrionCytosol

8 ALA synthase D-ALA ALA dehydrase PBG deaminase Hydroxymethylbilane NH2-CH2-COOH + Glycine PBG Water-soluble Excreted in urine Water-soluble Excreted in urine

9 Hydroxymethylbilane Uroporphyrinogen III URO I URO III synthaseSpontaneous Coproporphyrinogen III COPRO I URO III decarboxylase Less water-soluble Excreted in urine/feces Water-soluble Excreted in urine

10 CORPO III Protoporphyrinogen IX COPRO oxidase PROTO oxidase Protoporphyrin IX Ferrochelatase Heme Poor water-solubility Excreted in feces

11 Acute Porphyrias Acute Intermittent Porphyria Variegate Porphyria Hereditary Coproporphyria Porphyria Cutanea Tarda Congenital Erythropietic Porphyria Non-acute Porphyrias ALAD Deficiency Porphyria Secondary Porphyrias Lead Poisoning Iron Deficiency Coproporphyrinuria Glycine +Succinyl CoA ALA synthase ALA ALA dehydrase PBG PBG deaminase Hydroxymethylbilane URO IIIURO I URO III synthaseSpontaneous COPRO III COPRO I PROTO IX COPRO oxidase URO III decarboxylase PROTO oxidase Protoporphyrin IX Ferrochelatase Heme Erythropoietic Protoporphyria (Neurological Porphyrias) (Cutaneous Porphyrias) (Unstable) Main Types of Porphyria

12 Acute Porphyrias Acute Intermittent Porphyria Variegate Porphyria Hereditary Coproporphyria Porphyria Cutanea Tarda Congenital Erythropietic Porphyria Non-acute Porphyrias ALAD Deficiency Porphyria Secondary Porphyrias Lead Poisoning Iron Deficiency Coproporphyrinuria Erythropoietic Protoporphyria (Neurological Porphyrias) (Cutaneous Porphyrias) InheritanceTissue expression Liver Erythroid cells E, L Autosomal recessive Liver Autosomal dominant Autosomal recessive

13 Acute Porphyrias Acute Intermittent Porphyria Variegate Porphyria Hereditary Coproporphyria Porphyria Cutanea Tarda Congenital Erythropietic Porphyria Non-acute Porphyrias ALAD Deficiency Porphyria Secondary Porphyrias Lead Poisoning Iron Deficiency Coproporphyrinuria Glycine +Succinyl CoA ALA synthase ALA ALA dehydrase PBG PBG deaminase Hydroxymethylbilane URO IIIURO I URO III synthaseSpontaneous COPRO III COPRO I PROTO IX COPRO oxidase URO III decarboxylase PROTO oxidase Protoporphyrin IX Ferrochelatase Heme urine Erythropoietic Protoporphyria

14 Acute Porphyrias Acute Intermittent Porphyria Variegate Porphyria Hereditary Coproporphyria Porphyria Cutanea Tarda Congenital Erythropietic Porphyria Non-acute Porphyrias ALAD Deficiency Porphyria Secondary Porphyrias Lead Poisoning Iron Deficiency Coproporphyrinuria Glycine +Succinyl CoA ALA synthase ALA ALA dehydrase PBG PBG deaminase Hydroxymethylbilane URO III URO I URO III synthaseSpontaneous COPRO III COPRO I PROTO IX COPRO oxidase URO III decarboxylase PROTO oxidase Protoporphyrin IX Ferrochelatase Heme urine Erythropoietic Protoporphyria urine

15 Acute Porphyrias Acute Intermittent Porphyria Variegate Porphyria Hereditary Coproporphyria Porphyria Cutanea Tarda Congenital Erythropietic Porphyria Non-acute Porphyrias ALAD Deficiency Porphyria Secondary Porphyrias Lead Poisoning Iron Deficiency Coproporphyrinuria Glycine +Succinyl CoA ALA synthase ALA ALA dehydrase PBG PBG deaminase Hydroxymethylbilane URO IIIURO I URO III synthaseSpontaneous COPRO III COPRO I PROTO IX COPRO oxidase URO III decarboxylase PROTO oxidase Protoporphyrin IX Ferrochelatase Heme urine Erythropoietic Protoporphyria urine Urine feces urine

16 Acute Porphyrias Acute Intermittent Porphyria Variegate Porphyria Hereditary Coproporphyria Porphyria Cutanea Tarda Congenital Erythropietic Porphyria Non-acute Porphyrias ALAD Deficiency Porphyria Secondary Porphyrias Lead Poisoning Iron Deficiency Coproporphyrinuria Glycine +Succinyl CoA ALA synthase ALA ALA dehydrase PBG PBG deaminase Hydroxymethylbilane URO IIIURO I URO III synthaseSpontaneous COPRO III COPRO I PROTO IX COPRO oxidase URO III decarboxylase PROTO oxidase Protoporphyrin IX Ferrochelatase Heme urine Erythropoietic Protoporphyria urine Urine feces urine

17 Acute Porphyrias Acute Intermittent Porphyria Variegate Porphyria Hereditary Coproporphyria Porphyria Cutanea Tarda Congenital Erythropietic Porphyria Non-acute Porphyrias ALAD Deficiency Porphyria Secondary Porphyrias Lead Poisoning Iron Deficiency Coproporphyrinuria Glycine +Succinyl CoA ALA synthase ALA ALA dehydrase PBG PBG deaminase Hydroxymethylbilane URO III URO I URO III synthaseSpontaneous COPRO III COPRO I PROTO IX COPRO oxidase URO III decarboxylase PROTO oxidase Protoporphyrin IX Ferrochelatase Heme Erythropoietic Protoporphyria Urine Feces

18 Acute Porphyrias Acute Intermittent Porphyria Variegate Porphyria Hereditary Coproporphyria Porphyria Cutanea Tarda Congenital Erythropietic Porphyria Non-acute Porphyrias ALAD Deficiency Porphyria Secondary Porphyrias Lead Poisoning Iron Deficiency Coproporphyrinuria Glycine +Succinyl CoA ALA synthase ALA ALA dehydrase PBG PBG deaminase Hydroxymethylbilane URO IIIURO I URO III synthaseSpontaneous COPRO III COPRO I PROTO IX COPRO oxidase URO III decarboxylase PROTO oxidase Protoporphyrin IX Ferrochelatase Heme Erythropoietic Protoporphyria urineUrine Feces

19 Acute Porphyrias Acute Intermittent Porphyria Variegate Porphyria Hereditary Coproporphyria Porphyria Cutanea Tarda Congenital Erythropietic Porphyria Non-acute Porphyrias ALAD Deficiency Porphyria Secondary Porphyrias Lead Poisoning Iron Deficiency Coproporphyrinuria Glycine +Succinyl CoA ALA synthase ALA ALA dehydrase PBG PBG deaminase Hydroxymethylbilane URO IIIURO I URO III synthaseSpontaneous COPRO III COPRO I PROTO IX COPRO oxidase URO III decarboxylase PROTO oxidase Protoporphyrin IX Ferrochelatase Heme Erythropoietic Protoporphyria Feces

20 Acute Porphyrias Acute Intermittent Porphyria Variegate Porphyria Hereditary Coproporphyria Porphyria Cutanea Tarda Congenital Erythropietic Porphyria Non-acute Porphyrias ALAD Deficiency Porphyria Secondary Porphyrias Lead Poisoning Iron Deficiency Coproporphyrinuria Glycine +Succinyl CoA ALA synthase ALA ALA dehydrase PBG PBG deaminase Hydroxymethylbilane URO IIIURO I URO III synthaseSpontaneous COPRO III COPRO I PROTO IX COPRO oxidase URO III decarboxylase PROTO oxidase Protoporphyrin IX Ferrochelatase Heme Erythropoietic Protoporphyria Feces urine Urine Feces Zn-protoporphyrin

21 Acute Porphyrias Acute Intermittent Porphyria Variegate Porphyria Hereditary Coproporphyria Porphyria Cutanea Tarda Congenital Erythropietic Porphyria Non-acute Porphyrias ALAD Deficiency Porphyria Secondary Porphyrias Lead Poisoning Iron Deficiency Coproporphyrinuria Glycine +Succinyl CoA ALA synthase ALA ALA dehydrase PBG PBG deaminase Hydroxymethylbilane URO IIIURO I URO III synthaseSpontaneous COPRO III COPRO I PROTO IX COPRO oxidase URO III decarboxylase PROTO oxidase Protoporphyrin IX Ferrochelatase Heme Erythropoietic Protoporphyria Zn-protoporphyrin

22 Hepatic Porphyrias (normal RBC Porphyrins) Erythropoietic Porphyrias ( RBC Porphyrins) Acute Intermittent Porphyria (AIP)Congenital Erythropoietic Porphyria (CEP) Variegate porphyria (VP)Erythropoietic Protoporphyria (EP) Hereditary Coproporphyria (HCP) Porphyria Cutanea Tarda (PCT) Sunnybrook Health Sciences Center Sampling Guide Presentation:PorphyriasTests to orderSample Acute symptomsAIP1. Urine Porphyrin Precursors Screen & QuantitationRandom (50 ml) or 24-h with Tartaric acid Acute symptoms + skin lesions (may occur independently) VP HCP 2. Feces Porphyrins Screen & QuantitationRandom Skin lesionsPCT CEP EP 1. Urine Porphyrin Precursors Screen & Quantitation 2. Feces Porphyrins Screen & Quantitation 3. Urine Porphyrins Screen & Quantitation 4. RBC Porphyrins Screen & Quantitation Random (50 ml) or 24-h with Tartaric acid Random Random (50 ml) or 24-h with Na 2 CO3 Lavender-top (EDTA) blood; need Hct Notes: At time of acute attack: 1. Collect a random urine sample first (50 ml with no preservatives), before attempting to collect a 24-h sample. 2. Request "Porphyrin Precursors" (ALA & PBG) instead of "Porphyrins" screen and quantitation. The Laboratory will have to adjust pH to 4-6 for "Porphyrin Precursors", but pH 8-10 for "Porphyrins". - The commonest problem causing confusion! 3. All sample containers should be covered with tin foil to shield off from light.

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24 Test NameSpecimen TypeSearch / Alternate Name Porphyrin Precursors (ALA & PBG) Porphyrin Precursors (ALA & PBG) Urine (24h) ALA,Aminolevulinic Acid,PBG,Porphobilinogen, -ALA, - aminolevulinic Acid Porphyrin Precursors (ALA & PBG) Porphyrin Precursors (ALA & PBG) Urine (Random) ALA,Aminolevulinic Acid,PBG, -ALA,Porphobilinogen Porphyrins: Quantitation Porphyrins: Quantitation Urine (24h) Uroporphyrin,Heptacarboxylic Acid,Hexacarboxylic Acid,Pentacarboxylic Acid,Coproporphyrin Porphyrins: Quantitation Porphyrins: Quantitation Urine (Random) Uroporphyrin,Heptacarboxylic Acid,Hexacarboxylic Acid,Pentacarboxylic Acid,Coproporphyrin Porphyrins: Quantitation Porphyrins: Quantitation Whole blood (EDTA) Free Protoporphyrin,Protoporphyrin - Free Porphyrins: Quantitation Porphyrins: Quantitation Feces (Random) Coproporphyrin,Uroporphyrin,Heptacarboxylic Acid,Hexacarboxylic Acid,Pentacarboxylic Acid,Deuteroporphyrin,Mesoporphyrin,Protoporphyrin Porphyrins: Quantitation Porphyrins: Quantitation Plasma (EDTA or Heparin) Uroporphyrin,Heptacarboxylic Acid,Hexacarboxylic Acid,Pentacarboxylic Acid,Coproporphyrin Bio-Rad Column HPLC Porphyrin assays provided through HICL

25 Isocoproporphyrin Not Available - See Note. Porphobilinogen Deaminase Porphobilinogen Deaminase Whole blood (Heparin) Uroporphyrinogen 1 Synthetase,HMB,Hydroxymethylbilane Synthase Porphyrins: Screen Porphyrins: Screen Urine (24h) Porphyrins: Screen Porphyrins: Screen Feces (Random) Porphyrins: Screen Porphyrins: Screen Urine (Random) Zinc Protoporphyrin Zinc Protoporphyrin Whole blood (Heparin) ZPP,Metal ICP-MS Lead Whole blood (heparin) Pb,Zinc Protoporphyrin,ZPP,Metal Enzymatic Spectrophometric Screening

26 CASE A boy, average hematologic parameters over the subsequent 3 years were as follows: Defect in: Porphyrin synthesis Heme synthesis Globin synthesis microcytic Iron studies were unremarkable Hemoglobin (Hb) level, 70.0 g/L; Mean corpuscular volume (MCV), 67 fL Mean corpuscular hemoglobin level, consistently < 20 pg; Reticulocyte counts ranged from 3.6% to 6.7%;

27 A physical examination revealed scars on the face, hands, and forearms. photosensitive bullous dermatosis A 50-mL urine sample contained 2003 ug uroporphyrin (normal, trace); 92% of this was uro-I. CEP The diapers exhibited brilliant pink fluorescence when illuminated with long-range ultraviolet light. Photosensitive porphyrin rings Fluorescent red cells were detected using a microscope fitted with a 405 nm light source. CEP or EP Erythrocyte UROS activity was 21% of the normal mean. Collectively, these findings confirmed the diagnosis of CEP.

28 Erythrocyte UROS activity was normal in both parents, an unexpected finding as obligate carriers (heterozygotes) for UROS mutations generally have half- normal enzymatic activity. UROS was sequenced, and no mutations or deletions were found in the child or the parents. A GATA1 point mutation was found in the child at codon 216, changing arginine to tryptophan (R216W), as well as on 1 of the 2 GATA1 alleles of his mother and maternal grandmother. GATA1 gene, at Xp11.23, encodes a transcription factor, GATA binding factor 1 (GATA-1), that is critical for normal erythropoiesis, globin gene expression, and megakaryocyte development. GATA-1 also regulates expression of UROS in developing erythrocytes.

29 General Symptomology: __Abdominal pain ___Abdominal tenderness ___Loss of appetite ___Nausea ___Vomiting ___Constipation ___Carbohydrate craving ___Breast secretions ___Diarrhea ___Partial ileus [Intestinal blockage] ___Abdominal distention ___Dysuria [Painful Urination] ___Bladder Dysfunction ___Urinary Retention ___Amenorrhea [Lack of menses] Physical Findings of Acute Attack __Red or dark urine ___Tachycardia [Pulse] >100 ___Labile hypertension >90 diastolic [blood pressure] ___Fever [Pyrexia] ___Profused sweating ___Edema [Retention of fluids] [Swelling] ___Postural Hypotension [Low Blood Pressure] ___Hypertrichosis [excessive body hair growth] ___Hyperpigmentation [skin coloring]

30 Neurological Symptoms of Acute Attack [Peripheral manifestations] ___Peripheral neuropathy ___Muscle weakness ___Paresis. paralysis ___Sensory disorde ___Respiratory paralysis ___Foot drop ___Wrist drop ___Abnormal Gait ___Pain: Arms, legs, hips and/or lower back ___Loss of sensation ___Dyesthesia ___Numbness ___Tingling ___Burning Sensation ___Bulbar paresis ___Tongue paralization ___Mouth paralization ___Throat paralization [Cerebral manifestations] ___Behavorial change ___Anxiety ___Irritability ___Delirium ___Depression ___Confusion ___Hallucination ___Insomnia ___ANS [altered neurological state] ___Restlessness ___Sensory loss ___Seizure ___Depressed or absent tendon reflexes ___Cranial nerve involvement

31 Hematology/Blood Chemistry ___Hyponatremia [Below normal sodium level] 10,000 ___Increased ESR >22 ___Hypochloremia < 90 [A decrease in the chloride level] ___Anemia [Iron deficiency] Cutaneous manifestations ___Skin photosensitivity ___Blistering ___Severe Tissue Scarring ___Increased Hair growth ___Pigmentation Darkening ___Thickening of skin ___Severe Itching Special lab studies ___Decreased blood volume ___EEG abnormalities ___Electromyographic abnormalities ___Muscle denervation ___Decreased nerve conduction velocity ___Abnormal CSF ___Increased fibrillation potential


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